Attention-Deficit/Hyperactivity Disorder (ADHD) is a behavior disorder characterized by problems with control of attention and hyperactivity-impulsivity. The attentional difficulties and impulsivity associated with ADHD have been persuasively documented in laboratory investigations using cognitive tasks. Although these problems typically present together, one may be present without the other to qualify for a diagnosis (Am. Psychiatric Assoc. Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., Text Revision, 2000) (DSM-IV-TR). Generally, attention deficit or inattention becomes apparent when a child enters elementary school. A modified form of the disorder can persist into adulthood (Am. Psychiatric Assoc. Diagnostic and Statistical Manual of Mental Disorders, 3rd Ed., 1987). With respect to the attention component, the child is easily distracted by outside stimuli, neglects finishing tasks, and has difficulty maintaining attention. Regarding the activity component, the child is often fidgety, impulsive, and overactive. The symptoms of ADHD may be apparent as young as preschoolers and are virtually always present prior to the age of 7 (Halperin et al., J. Am. Acad. Child Adolescent Psychiatry, 32:1038-1043, 1993).
According to the DSM-IV-TR, diagnostic criteria for Attention-Deficit/Hyperactivity Disorder relate to symptoms associated with inattention and/or hyperactivity-impulsivity. Three subtypes of ADHD are diagnosed based on the predominant symptoms presented.
Many of the symptoms that are characteristic of ADHD occur occasionally in normal children. Children with ADHD, however, exhibit these symptoms frequently, which tends to interfere with the child's day to day functioning. Such children are often challenged by academic underachievement because of excitability and impaired interpersonal relationships.
ADHD affects 2-6% of grade school children. Pediatricians report that approximately 4% of their patients have ADHD; however, in practice the diagnosis is made in children who meet several, but not all of the diagnostic criteria that is recommended in DMS-IV-TR (Wolraich et al., Pediatrics, 86(1):95-101, 1990). Boys are four times more likely to have the disorder than girls and the disorder is found in all cultures (Ross & Ross, Hyperactivity, New York, 1982).
Psychomotor stimulants are the most common treatment for ADHD. Safer & Krager (1988) reported that 99% of the children with ADHD were treated with stimulants, of which 93% were given methylphenidate hydrochloride (Ritalin), and the remainder were given dextroamphetamine sulfate (d-amphetamine) or pemoline (Safer & Krager, J.A.M.A., 260:2256-2258, 1988). Four separate psychostimulant medications consistently reduce the central features of ADHD, particularly the symptoms of inattention and ADHD associated hyperactivity-impulsivity: methylphenidate, d-amphetamine, pemoline, and a mixture of amphetamine salts (Spender et al., Arch. Gen. Psychiatry, 52:434-443, 1995). These drugs block uptake sites for catecholamines on presynaptic neurons or stimulate the release of granular stores of catecholamines. They are metabolized and leave the body fairly rapidly, and have a therapeutic duration of action of 1 to 4 hours. The psychostimulants do not appear, however, to make long-term changes in social or academic skills (Pelham et al., J. Clin. Child Psychology, 27:190-205, 1998). Stimulants are generally started at a low dose and adjusted weekly. Common stimulant side effects include insomnia, decreased appetite, stomachaches, headaches, and jitteriness. Psychostimulants also have the potential for abuse, because they are addictive. Thus, current methods of treating ADHD provide inadequate treatment for some patients and/or have side effects that limit their usefulness.
Children who cannot tolerate psychostimulants often use the antidepressant bupropion. While bupropion is not as effective as stimulants, it may be used as an adjunct to augment stimulant treatment.
Castellanos et al. concluded that ADHD is a genetically programmed disorder of brain development resulting from altered function of the frontal-striatal-pallidal-thalamocortical loops which regulate cognitive processes, attention, and motor output behaviors (Castellanos et al., Arch. Gen. Psychiatry, 53: 607-616, 1996). Although the precise etiology of ADHD is unknown, neurotransmitter deficits, genetics, and perinatal complications have been implicated.
Individuals with ADHD have been reported to have impairments in their ability to perceive intervals of time (Conners & Levin, Psychopharmacol. Bulletin, 32(1):67-73, 1996). Time perception is a useful measure of cognitive function, sensitive to dopaminergic and cholinergic manipulations in animals and humans. As in all behavioral tasks, several processes underlie good steady state performance in a temporal task. These behavioral tasks include: attention, motivation, short and long term memory, motor coordination, and instrumental learning. Scaling, discrimination, and reproduction are the three main types of temporal tasks that have been identified. In scaling, subjects must, for example, categorize a stimulus into a given set of categories (“that was a long duration”) or verbally estimate the duration (“that was a 4 s duration”). In discrimination a comparison is made between two durations (“the second stimulus was longer than the first”). Finally, in reproduction a response is made that bears some relation with the stimulus (e.g. only responses that are as long or longer than the stimulus are correct).
Time perception is a particularly effective measure for testing cognitive deficits in ADHD individuals. For example, Conners & Levin (1996) showed that ADHD adults improve in measures of attention and timing with the administration of nicotine. Nicotine, like the psychostimulants methylphenidate and d-amphetamine, acts as an indirect dopamine agonist and improves attention and arousal. Studies indicate that adults and adolescents with ADHD smoke much more frequently than normal individuals or those with other psychiatric conditions, perhaps as a form of self-medication for ADHD symptoms. The results indicated that there was a significant clinician-rated global improvement, self-rated vigor and concentration, and improved performance on chronometric measures of attention and timing accuracy, and side effects were minimal (Conners & Levin, supra).
Eltoprazine hydrochloride [1-(2,3-dihyro-1,4-benzodioxin-5-yl) piperazine hydrochloride], a phenylpiperazine derivative, was originally developed as a “serenic.” “Serenics” are drugs developed for the selective treatment of aggressive behavior, without negatively affecting general functioning or motor abilities, and which demonstrate minimal side effects. Thus, eltoprazine was developed to treat and manage inappropriate aggression with high specificity. While unsuccessful in clinical trials, eltoprazine did prove to be clinically safe (de Koning et al., Int. Clin. Psychopharmacol., 9:187-194, 1994).
It has been hypothesized that the mechanism of action for eltoprazine in aggression is associated with activation of central serotonergic (5-hydroxytryptophan, 5-HT) systems (Schipper, J. et al., Drug Metabolism & Drug Interactions, 8:85-114, 1990). In adults, central 5-HT neurotransmission is inversely correlated with aggression: diminished 5-HT function is associated with increased aggression. However, such a relationship is reported to be non-existent in children, including those having ADHD (Schulz et al., Psychiatry Res., 101:1-10, 2001).
At present, seven main 5-HT receptor classes have been identified: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7. Radioligand binding studies have revealed at least five subtypes of the 5-HT1 receptor (1A, 1B, 1D, 1E and 1F). Because the 5-HT1B receptors are present in the hippocampal formation, it has been suggested that a potential role for these receptors is the modulation of memory processes (Malleret, J. Neurosci., 19:6157-68, 1999). Serotonin inhibits acetylcholine release through 5-HT1B receptors located on septal terminals in the hippocampus (Maura and Raiteri, Eur. J. Pharmacol., 129:333-337, 1986) and glutamate release in the dorsal subiculum through 5-HT1B receptors located on CA1 pyramidal neuron terminals (Aït Amara et al., Brain Res. Bulletin, 38(1):17-23, 1995). Stimulation of the hippocampal receptors in rats resulted in impaired spatial learning tasks and neophobic reactions in an object exploration task (Buhot and Naili, Hippocampus, 5:198-208, 1995). Thus, the blockade of 5-HT1B receptors potentially affects attention and emotion and positively affects learning and memory processes (Buhot et al., supra). Therefore, 5-HT1B agonists would be predicted not to enhance attention or cognitive function.
The binding profile of eltoprazine, together with the direct binding data obtained with [3H] eltoprazine, shows the compound to be a selective 5-HT1 ligand (selective with respect to all receptors other than 5-HT1). Eltoprazine's binding affinity for the various 5-HT receptor subtypes closely resembles serotonin except for the relatively low affinity for the 5-HT1D receptor with roughly equipotent affinity for the 5-HT1A, 5-HT1B, and 5-HT2C receptors (Schipper, J. et al., supra). Eltoprazine acts as a mixed 5-HT1A/1B receptor agonist. Eltoprazine has no relevant affinity for dopamine receptors (i.e., K1>1 μM, Schipper et al., supra). Among the 5-HT receptors, the 5-HT1B is located as an autoreceptor on axon terminals and is responsible for inhibiting neurotransmitter release, whereas it is also located postsynaptically as a heteroreceptor on axons and terminals of non-serotonergic neurons inhibiting their activity.
Pharmacokinetic studies have indicated that eltoprazine HCl is very well absorbed, with an absolute bioavailability of about 95%. The maximum plasma concentration of eltoprazine is attained within 1-4 hours after administration, followed by a decrease in plasma concentration with a terminal half-life of 7-9 hours. The cumulative renal excretion of unchanged eltoprazine is about 40%. The plasma elimination half-life ranges between 5-12 hours. Eltoprazine plasma concentrations increase in a linear dose-dependent manner (De Vries et al., Clinical Pharmacology, 41:485-488, 1991).